Many ways to telomere dysfunction: in vivo studies using mouse models

The existence of a capping structure at the extremities of chromosomes was first deduced in the 1930s by Herman Müller (Müller, 1938), who showed that X-irradiation of Drosophila rarely resulted in terminal deletions or inversions of chromosomes, suggesting that chromosome ends have protective structures that distinguish them from broken chromosomes, which he named telomeres. In this review, we will focus on mammalian telomeres and, in particular, on the analysis of different mouse models for proteins that are important for telomere function, such as telomerase and various telomere-binding proteins. These murine models are helping us to understand the consequences of telomere dysfunction for cancer, aging and DNA repair, as well as, the molecular mechanisms by which telomeres exert their protective function.     

Further comparisons of ABR response amplitudes,test time,and estimation of hearing threshold using frequency-specific chirp and tone pip stimuli in newborns: Findings at 0.5 and 2 kHz

Objective: To compare auditory brainstem response (ABR) amplitudes evoked by 0.5 and 2 kHz tone pip and narrowband chirp (NB CE-Chirp) stimuli when testing post-screening newborns. To determine the difference in ‘estimated hearing level’ correction values. Design: Tests were performed with tone pips and NB CE-Chirps at 0.5 or 2 kHz and the ABR threshold for each stimulus defined. Response amplitude, response quality (Fmp), and residual noise were compared for both stimuli. Study sample: Thirty-nine babies (42 ears) who passed our ABR discharge criterion at 4 kHz following referral from their newborn hearing screen. Results: NB CE-Chirp responses were, on average, 31% larger than the tone pip responses at 0.5 kHz and were 52% larger at 2 kHz. Fmp was significantly higher for NB CE-Chirps. Conclusions: The advantages of NB CE-Chirps over tone pips we previously identified at 4 and 1 kHz extends to 0.5 and 2 kHz, which supports the use of NB CE-Chirps when testing newborns. We propose that ABR nHL threshold to eHL corrections for NB CE-Chirps should be approximately 5 dB less than corrections for tone pips at 0.5 and 2 kHz, mirroring our recommendation at 4 and 1 kHz.     

Increased visceral fat accumulation modifies the effect of insulin resistance on arterial stiffness and hypertension risk

Background and aimsBoth insulin resistance (IR) and visceral adipose tissue (VAT) are related cardiometabolic risk factors; nevertheless, their joint effect on endothelial functionality is controversial. This study aims to evaluate the joint effect of IR and VAT on endothelial functionality using the pulse-waveform analysis and explore the mediating role of VAT on the effect of IR on arterial pressure, arterial stiffness and incident arterial hypertension.Methods and resultsWe measured VAT (n = 586) using two methods (dual-energy X-ray absorptiometry and a clinical surrogate), arterial stiffness (with pulse-waveform velocity), and IR (using three methods: HOMA2-IR (n = 586), a frequently sampled intravenous glucose tolerance test (n = 131) and euglycemic hyperinsulinemic clamping (n = 97)) to confirm the mediator effect of IR on VAT. The incidence of arterial hypertension attributable to the mediating effect of IR related to VAT was evaluated using a prospective cohort (n = 6850). Adjusted linear regression models, causal mediation analysis, and Cox-proportional hazard risk regression models were performed to test our objective. IR and VAT led to increased arterial stiffness and increased blood pressure; the combination of both further worsened vascular parameters. Nearly, 57% (Δ_E→MY 95% CI: 31.7–100.0) of the effect of IR on altered pulse-wave velocity (PWV) analysis was mediated through VAT. Moreover, VAT acts as a mediator of the effect of IR on increased mean arterial pressure (Δ_E→MY 35.7%, 95% CI: 23.8–59) and increased hypertension risk (Δ_E→MY 69.1%, 95% CI: 46.1–78.8).ConclusionVAT acts as a mediator of IR in promoting arterial stiffness and arterial hypertension. Both phenomena should be targeted to ameliorate the cardiometabolic risk.     

The intestinal anti-inflammatory activity of UR-12746S on reactivated experimental colitis is mediated through downregulation of cytokine production

BACKGROUND: UR-12746S (dersalazine sodium) is cleaved by colonic bacteria delivering the PAF antagonist UR-12715 and 5-ASA. This study describes the anti-inflammatory activity of UR-12746S in an experimental model of reactivated colitis and its effects on cytokine production. METHODS: Rats were initially rendered colitic by a colonic instillation of 10 mg of trinitrobenzenesulphonic acid (TNBS) dissolved in 0.25 ml of 50 % ethanol, and colitis was reactivated two weeks after by a second administration of the same dose of TNBS. Two groups of colitic rats received UR-12746S (25 and 50 mg/kg daily, p.o.) and colonic damage was evaluated every week for 4 weeks. Different biochemical markers of colonic inflammation were assayed: MPO activity and cytokine (IL-1beta and TNFalpha) levels. Also, the in vitro effects of UR-12715 and 5-ASA on cytokine production were assayed. RESULTS: UR-12746S showed anti-inflammatory effect in reactivated colitis in rats, as evidenced by a significant reduction in MPO activity. Both doses of UR-12746S decreased IL-1beta production, while only the highest dose assayed inhibited TNFalpha production. In vitro studies revealed that UR-12715 or 5-ASA (from 10(-6) to 10(-4) M) inhibited IL-8 production (30-40%) in HT-29 cells when incubated with LPS. This inhibitory effect was enhanced when both compounds were administered simultaneously at 10(-4) M. In addition, UR-12715 inhibited IL-1beta or TNFalpha production in THP-1 or U937 cells, respectively, when these cells were stimulated by PMA and LPS; whereas 5-ASA only showed a weak effect in inhibiting IL-1beta production. CONCLUSION: UR-12746S was able to prevent relapse in experimental colitis and inhibition of proinflammatory cytokine production participates in the intestinal anti-inflammatory activity exerted by this compound.     

Short Communication: RNASEL Alleles and Susceptibility to Infection by Human Retroviruses and Hepatitis Viruses

Abstract RNASEL seems to function as an intracellular restriction factor blocking the establishment of infections caused by viral agents. Herein, we investigated whether allelic variants at the RNASEL gene might influence the susceptibility to viral infections or conditions potentially linked to viral agents. The allelic distribution at codon 462 was 139 (33.9%), 204 (49.8%), and 67 (16.3%) for RR, RQ, and QQ, respectively, in 410 individuals in Spain. There were no significant differences comparing 105 blood donors and 71 patients with HIV-1 infection, 27 with chronic hepatitis C, 67 with prostate cancer, and 107 with chronic fatigue syndrome. In contrast, two-thirds of 18 patients with HTLV-1 infection and 15 with chronic hepatitis B harbored RR. Thus, polymorphisms at the RNASEL gene do not seem to influence the susceptibility to common viral infections or conditions potentially of viral etiology. The role in influencing the susceptibility to HTLV-1 or HBV chronic infection warrants further examination in larger patient populations.     

Prevalence of xenotropic murine leukemia virus-related virus infection in different risk populations in Spain

Human infection with the xenotropic murine leukemia virus-related virus (XMRV) has been associated controversially with prostate cancer and chronic fatigue syndrome. Information is lacking about the mechanisms of transmission and potential risk groups for XMRV infection. Plasma and peripheral blood mononuclear cells (PBMCs) from individuals with retroviral infections, chronic viral hepatitis, autoimmune diseases, prostate cancer, chronic fatigue syndrome, and blood donors were tested for XMRV markers. Antibodies to XMRV proteins p15E and gp70 were examined using research assays. DNA extracted from PBMCs was tested for the presence of XMRV gag and env sequences. A total of 1103 specimens belonging to individuals with chronic fatigue syndrome and/or fibromyalgia (437), prostate cancer (69), HIV-1 (149), HTLV-1/2 (31), chronic hepatitis B (81), chronic hepatitis C (72), autoimmune diseases (18), and blood donors (246) were examined. Overall, three samples (0.3%) were p15E seroreactive (two HTLV-1 and one HCV patient). Another 15 (1.4%) were gp70 seroreactive (six chronic fatigue syndrome-fibromyalgia, four blood donors, two HIV-1, one prostate cancer, one HBV, and one HCV). Four specimens were initially positive for XMRV gag sequences, but none could be confirmed by repeated testing. In summary, no evidence of XMRV infection was found in populations with retroviral and viral hepatitis infections in Spain. Likewise, XMRV was not recognized in patients with autoimmune diseases, chronic fatigue syndrome-fibromyalgia, prostate cancer, or healthy blood donors.     

Dietary fat and antioxidant vitamin intake in patients of neurodegenerative disease in a rural region of Jalisco,Mexico

Objective

To evaluate and compare the intake of lipids and (A, E, and C) vitamins in patients with and without possible neurodegenerative diseases.

Methods

Twenty adults with possible Alzheimer's disease or Parkinson's disease and 41 control subjects (50–89 years old) from a rural region were studied. Dietary intake was evaluated with the analysis of macronutrients and micronutrients conducted by a food frequency questionnaire and 24 hours dietary record. Analyses were adjusted for age, sex, body mass index, and energy intake. Through interrogation and use of medical record form of health secretary we obtained information about the sociodemographic characteristics. Multivariate analysis of variance to allow for covariated adjustment was used.

Results

Patients had a lower energy intake, vitamin C (P = 0.016), fruits (P < 0.001), vegetables (P = 0.037), and oils and fat (P = 0.002), than the controls. Interestingly, the C vitamin intake in patients was still higher than the recommended. Patients had a higher consumption of cereals (P = 0.017), high-animal fat diet (P = 0.024), and whole milk (P < 0.001); 2.4% of the controls smoke and 5% are alcohol consumers. Eighty-five percent of patients and 78% of the controls do not have physical activity. Family history of subjects in this study indicated chronic diseases.

Conclusion

The subjects included in this study had a high intake of C vitamin, this is due to the consumption of fruits and vegetables. However, patients with possible Alzheimer's or Parkinson's disease had a lower intake of fruits and vegetables, which could be due to type of food to which they have access.